This report incorporates former reports: AA000208-07, AA000204-02, AA000207-04, AA000205-03. The following projects are being conducted by CATE. Each study employs a number of dependent measures that are designed to study pathology and measure treatment efficacy. Recruitment is protocol-driven and is frequently aimed at specific patient populations such as non-treatment seeking heavy drinkers, anxious alcoholics, and alcoholics with a history of post traumatic stress disorder. The participant meets with their primary nurse and their physician on a regular basis to facilitate their recovery and to attend to the protocol specific interventions. Participants are encouraged to be followed in the NIAAA outpatient program which incorporates medication management as well as individual and group therapies. 1.) Clinical trial of SR141716, Rimonabant, to reduce voluntary ethanol consumption: The main endocannabinoid receptor subtype, the CB1 receptor, is widely distributed in the brain. Endocannabinoids act presynaptically in the CNS to modulate the release of various neurotransmitters such as dopamine, GABA, and glutamate. In the limbic forebrain, they are involved with motivational aspects of feeding such as desire and reward. Mice which lack the CB1 receptor drink significantly less alcohol than their wild-type littermates;administration of rimonabant reduces ethanol drinking in the wild-type but not the CB1 receptor deficient mice. Based on an extensive animal literature implicating the endocannabinoid system in alcoholism, we investigated whether the CB1 cannabinoid receptor antagonist rimonabant, compared to placebo, would reduce alcohol consumption in heavy drinkers. Participant enrollment and data analyses for this study have been completed. The number of drinks consumed during the alcohol self-administration paradigm did not differ between rimonabant and placebo groups. None of the measures addressed in this protocol were able to predict which of the participants would be motivated to change their drinking behaviors. Currently, a manuscript is being revised for publication in Psychopharmacology. 2.) Pharmacologically induced alcohol craving in detoxified alcoholics: Craving is a key element in the relapse process;therefore, craving is an important surrogate marker that can be used to evaluate the potential effectiveness of medications to treat alcohol dependent patients. It is well established that craving can be induced in response to experimental stimuli that attempt to mimic real-world relapse triggers, such as experimental stressors or alcohol-associated cues. To test the effectiveness of acamprosate in reducing pharmacologically-induced alcohol craving in alcohol dependent participants, we are utilizing a double-blind, placebo-controlled paradigm in which we administer: 1) an alpha 2-adrenergic antagonist (Yohimbine) which reliably induces reinstatement of alcohol seeking behavior in experimental animals, 2) a serotonergic compound (mCPP) which robustly increases alcohol craving in human alcoholics, and 3) placebo. We are currently recruiting participants for this protocol. 3.) Effect of Acamprosate on CNS hyperexcitability in alcohol withdrawal: Clinical as well as preclinical studies indicate that the process for developing alcohol dependence involves a hyperglutamatergic state, which is thought to be a signal for emotional deregulations leading to craving and relapse, as well as neurotoxicity leading to cognitive impairment and loss of brain grey matter in alcoholic patients. Preclinical data indicate that acamprosate might be a useful agent to target the hyperglutamatergic state that develops during recurring episodes of withdrawal. The primary objective of this protocol is to evaluate, using a randomized controlled trial, the effects of acamprosate administration, during withdrawal and the early post withdrawal period, on brain glutamate/glutamine concentrations, as measured by NMR proton spectroscopy. In addition, we will determine if acamprosate administration affects CSF indices of glutaminergic activity. Participant accrual has been completed for this project and a manuscript has been submitted for publication. 4.) Effect of Naltrexone on Craving and Ethanol-Induced Brain Activity: Findings from animal and human studies indicate that the rewarding properties of ethanol arise in part from a complex interaction between alcohol, endogenous opiods, and dopamine (DA) systems. Acute administration of ethanol increases the release of opioid peptides, which in turn, increases the release of DA in the mesocorticolimbic system. Naltrexone (NTX), an opioid receptor antagonist, has been studied widely in both preclinical and clinical research for the treatment of alcoholism. Numerous clinical studies have shown that short-term use of NTX in alcohol-dependent patients effectively prevents relapse and reduces the level of craving. This protocol is the first study which involves administering IV alcohol to treatment-seeking alcohol dependent patients. Following detoxification, patients are randomized, using a double-blind design, to receive NTX or placebo throughout the course of their hospitalization. fMRI scans involving ethanol infusions are performed to investigate the effects of Naltrexone on the blood oxygen level dependent response. We are currently recruiting participants for this protocol. 5.) Effect of NK1R Antagonism on Alcohol Craving and PTSD Symptoms in Alcohol Dependent Patients with PTSD: Alcoholism is highly co-morbid with post traumatic stress disorder (PTSD). Since stress and negative affective states are major relapse triggering factors for alcohol use, the negative symptoms associated with PTSD are thought to promote alcohol dependence. Substance P, which is released in the amygdala in response to stress, acts at NK1 receptors (NK1Rs) to mediate behavioral stress responses. Blockade of the NK1R represents a novel approach for anti-stress actions. In a recent double blind, placebo controlled study involving detoxified anxious alcoholics, we found that NK1R antagonism decreased alcohol cravings, attenuated cortisol response to stress, and significantly decreased insula activation in response to negative sensory input. The present study is intended to expand these findings and determine whether the NK1R is a candidate target for treating alcohol dependent patients with PTSD. We will soon be recruiting participants for this protocol.